Model of the tumor suppressor mechanism localized in 13q14.3.

<p>(A) Regions in CpG islands D and E that are DNA-methylated in non-malignant B-cells (left) become demethylated in the vast majority of CLL patients (right). This coincides with relaxed chromatin characterized by absence of macroH2A and enrichment of H3K4me2 at the promoters of the lncRNA genes <i>DLEU1</i> and <i>DLEU2/Alt1</i>. (B) DNA-hypomethylation is correlated with transcriptional upregulation of splicing variants of the two lncRNA genes <i>DLEU1</i> and <i>DLEU2</i> and inversely correlated with the protein-coding genes in 13q14.3. No correlation could be found with levels of mature <i>miR-15a</i> and <i>miR-16</i>, probably because these transcripts are also deregulated by a posttranscriptional processing defect in CLL cells (Allegra, manuscript submitted). (C) Candidate genes localized in the critical region in 13q14.3 are functionally related and all modulate NF-kB signalling, albeit with different impact. Nuclear transporter KPNA3 is binding NF-kB components p65 and p50 and is therefore likely a positive regulator like e.g. RFP2. RFP2 binds to C13ORF1 and induces NF-kB activity via the canonical pathway components p50 and p65, for which its ubiquitin ligase actvity is required. The miRNA genes <i>miR-15a</i> and <i>miR-16-1</i> were identified together with other members of this miR family to be among the strongest activators of NF-kB activity. Previously they have been shown to both modulate cell cycle regulators and inhibit NF-kB via <i>TAB3/TAK1. DLEU7</i> has recently also been reported to inhibit NF-kB by binding and inactivating the <i>TACI/BCMA</i> receptors.